Cytokine signals play an essential role in lymphocyte function and development. Disregulation of these signals can impede T cell development and lead to autoimmunity. Recent studies show that individuals possessing mutated cytokine receptor genes exhibit severe immunodeficiency syndromes (XSCID). The common gamma chain (Gc) is part of the IL-2, IL-4, IL-7, IL-9 and IL-15 receptor complexes. Through its ability to associate with kinases and other molecules, it transduces signals important for lymphocyte function. To examine the role of Gc-mediated signals, mice were generated in which the gene encoding Gc was inactivated by homologous recombination. Examination of these mice demonstrated that lymphocyte development, particularly T cell development, was affected. Unexpectedly, numbers of CD4+ cells increased with age, suggesting a defect in the normal mechanisms of lymphocyte homeostasis. In the past year, we have investigated the mechanism underlying this increase. We have found that these cells have an activated phenotype. Using T cell receptor transgenic mice we found that this activation is antigen specific, suggesting that unregulated responses to self antigen drives this expansion. Despite the CD4 accumulation, we found that cells from these mice had an augmented rate of apoptosis. However, since the CD4+ T cells accumulate, the rate of expansion must exceed the rate of cell death. These data demonstrate that signals mediated by Gc play a critical role in homeostasis and regulate the conflicting processes of expansion and cell death. Development of this animal model should be important in understanding the role of cytokines in autoimmune disease and lymphocyte reconstitution where the establishment or re-establishment of lymphocyte homeostasis is critical. More importantly, these animals provide a model to test therapies directed toward the treatment of Gc-mediated immune deficiency in humans. 1. Cao, X, Shores, E.W., et. al. 1995. Immunity 2:223. 2. Leonard, W.J., E.W. Shores, et al. 1995 Immunol. Rev.148:97. 4. Nakajima, H., Shores, E.W, M. Noguchi, W.J. Leonard, 1996, J.Exp.Med.